Efficacy Study Of Tofacitinib In Pediatric JIA Population

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This is a randomized withdrawal, double blind, placebo controlled study of pediatric subjects (2 to <18 years of age) with JIA. The primary objective is to compare the efficacy of tofacitinib versus placebo for the treatment of signs and symptoms of JIA at Week 26 of the double blind phase as measured by the percentage of subjects with disease flare (according to PRCSG/PRINTO Disease Flare criteria) after Week 18 of the open label run in phase.All eligible subjects enrolled in the study will initially receive open label tofacitinib for 18 weeks (run in phase). At the end of the 18 week run in phase, only subjects who achieve at least a JIA ACR 30 response will be randomized to the 26 week double blind, placebo controlled phase. Subjects who do not achieve a JIA ACR 30 response at this time point will be discontinued from the study. In addition, subjects who experience a single episode of disease flare at any time during the study (including the open label run in and double blind phase) will also be discontinued from the study. All subjects participating in this study, including those discontinued from the study, will have the option, if eligible (based on inclusion and exclusion criteria), of enrolling in the tofacitinib JIA long term extension study (A3921145).

Subjects who are eligible for the 26 week double blind phase will be randomized (1:1 ratio) to either active tofacitinib or placebo. For subjects with polyarticular course JIA (ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF , systemic JIA with active arthritis but without active systemic features), randomization will be stratified by JIA category and baseline CRP (normal, above normal). For subjects with psoriatic and enthesitis related arthritis, randomization will be stratified by JIA category.

Approximately 210 subjects will be enrolled in the open label run in phase. Among subjects with polyarticular course JIA, stratification will target at least 50% with a baseline CRP above the upper limit of normal. The first cohort (ie, polyarticular course JIA) will have at least 170 subjects enrolled in the run in phase with the minimum number of JIA categories as follows: 24 with extended oligoarthritis, 20 with polyarthritis RF+, 62 with polyarthritis RF-, and no minimum for subjects with systemic JIA with active arthritis but without active systemic features. Additional cohorts (ie, psoriatic and enthesitis related arthritis) will include a minimum of 20 subjects with psoriatic arthritis, and 20 subjects with enthesitis related arthritis. The overall target minimum number of subjects to be enrolled in the study by age is as follows: 20 subjects 2 to <6 years, 20 subjects 6 to <12 years, and 20 subjects 12 to <18 years. The duration of subject participation among those who complete the study (without discontinuation) is expected to be approximately 44 weeks.

During the open label run in phase, all subjects will receive active tofacitinib oral tablets or oral solution twice daily (BID) orally, at a dosage based on the subject's body weight as specified below.

JIA ACR50 response defined as: >=50% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

JIA ACR30 response defined as: >=30% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

JIA ACR70 response defined as: >=70% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

CHAQ is a valid assessment of functional disability, discomfort in participants with rheumatic diseases. It comprises of three indices: Disability and Discomfort, and global assessment of arthritis (overall well-being). CHAQ-DI: as a measure of functional ability, consists of 30 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities-distributed, among a total of 30 items. Each question was rated on a 4-point scale of difficulty in performance ranges from 0 (no difficulty) to 3 (unable to do). To calculate the overall score, the participant must have a domain score in at least 6 of the 8 domains. Scores of 8 domains were averaged to calculate the CHAQ-DI total score which ranges from 0 (no or minimal physical dysfunction) to 3 (very severe physical dysfunction), higher score indicates more disability. Change from double-blind baseline at Week 44 in DI total score is reported.

According to PRCSG/PRINTO, disease flare defined as worsening of >=30% in >=3 of 6 variables of JIA core set, with no more than 1 variable improving by >=30%. Six core variables were: 1) Number of joints with active arthritis (joint with swelling or in absence of swelling, limited range of motion accompanied by pain/ tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

According to PRCSG/PRINTO, disease flare defined as worsening of >=30% in >=3 of 6 variables of JIA core set, with no more than 1 variable improving by >=30%. Six core variables were: 1) Number of joints with active arthritis (joint with swelling or in absence of swelling, limited range of motion accompanied by pain/ tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

Open-Label Phase: Time to Disease Flare [ Time Frame: Day 1 up to week 18 ]

Time to disease flare:time (in days) from first dose of study drug until the day of disease flare in open-label phase. According to PRCSG/PRINTO, disease flare: worsening of >=30% in >=3 of 6 variables of JIA core set, with no more than 1 variable improving by >=30%. 6 core variables were: 1) Number of joints with active arthritis (joint with swelling or in absence of swelling, limited range of motion accompanied by pain/ tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

Double Blind Phase: Time to Disease Flare [ Time Frame: Day 1 of Week 19 up to week 44 ]

Time to disease flare: time (in days) from first dose of study drug until the day of disease flare in double blind phase. According to PRCSG/PRINTO, disease flare: worsening of >=30% in >=3 of 6 variables of JIA core set, with no more than 1 variable improving by >=30%. 6 core variables were: 1) Number of joints with active arthritis (joint with swelling or in absence of swelling, limited range of motion accompanied by pain/ tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

JIA ACR30 response defined as: >=30% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

JIA ACR30 response defined as: >=30% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

JIA ACR50 response defined as: >=50% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

JIA ACR50 response defined as: >=50% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

JIA ACR70 response defined as: >=70% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

JIA ACR70 response defined as: >=70% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

JIA ACR90 response defined as: >=90% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction); 6) ESR.

JIA ACR90 response defined as: >=90% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

JIA ACR100 response defined as: >=100% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

JIA ACR100 response defined as: >=100% improvement in 3 out of 6 JIA core set variables with no more than 1 out of 6 JIA core set variables worsened by >=30%. Six core variables: 1) Number of joints with active arthritis (defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 2) Number of joints with limited range of motion, 3) Physician global evaluation of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 4) Parent/legal guardian/participant global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor], 5) CHAQ-DI: 30 questions in 8 domains, each question answered on scale of 0=without difficulty to 3=unable to do; scores of each domain were averaged to derive total CHAQ-DI score, which ranges from 0 (minimum dysfunction) to 3 (most severe dysfunction);6) ESR.

JADAS-27 is a validated composite disease activity measure for JIA. JADAS-27 CRP score was derived from four components; 1) Physician global assessment of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 2) Parent/legal guardian/subject global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease(defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 4) CRP (measured in milligram per liter [mg/L] and value normalized to 0 to 10 scale). The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

JADAS-27 is a validated composite disease activity measure for JIA. JADAS-27 CRP score was derived from four components; 1) Physician global assessment of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 2) Parent/legal guardian/subject global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease(defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 4) CRP (measured in mg/L and value normalized to 0 to 10 scale). The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

JADAS-27 is a validated composite disease activity measure for JIA. JADAS-27 ESR score was derived from four components; 1) Physician global assessment of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 2) Parent/legal guardian/subject global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease (maximum of 27 and defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 4) ESR. The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

JADAS-27 is a validated composite disease activity measure for JIA. JADAS-27 ESR score was derived from four components; 1) Physician global assessment of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 2) Parent/legal guardian/subject global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease (maximum of 27 and defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 4) ESR. The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

Minimum Disease Activity is defined by a JADAS-27 CRP score less than or equal to 3.8 for participants with polyarthritis, and less than or equal to 2 for participants with oligoarthritis. JADAS-27 is a validated composite disease activity measure for JIA. JADAS-27 CRP score was derived from four components; 1) Physician global assessment of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 2) Parent/legal guardian/subject global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease(maximum of 27 defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 4) CRP (measured in milligram per liter [mg/L] and value normalized to 0 to 10 scale). The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

Minimum Disease Activity is defined by a JADAS-27 CRP score less than or equal to 3.8 for participants with polyarthritis, and less than or equal to 2 for participants with oligoarthritis. JADAS-27 is a validated composite disease activity measure for JIA. JADAS-27 CRP score was derived from four components; 1) Physician global assessment of disease activity (assessed on a VAS of 0 [no activity] to 10 [maximum activity]), 2) Parent/legal guardian/subject global assessment of overall well-being (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease (maximum of 27 and defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness), 4) CRP (measured in milligram per liter [mg/L] and value normalized to 0 to 10 scale). The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity.

Number of joints with active arthritis defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness. The score range of the number of joints is from 0-71.

Number of joints with active arthritis defined as joint with swelling or, in absence of swelling, limited range of motion accompanied by either pain on motion or tenderness. Number of joints ranged from 0 to 71.

CHAQ is a valid assessment of functional disability, discomfort in participants with rheumatic diseases. It comprises of three indices: Disability and Discomfort, and global assessment of arthritis (overall well-being). CHAQ-DI: as a measure of functional ability, consists of 30 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities-distributed, among a total of 30 items. Each question was rated on a 4-point scale of difficulty in performance ranges from 0 (no difficulty) to 3 (unable to do). To calculate the overall score, the participant must have a domain score in at least 6 of the 8 domains. Scores of 8 domains were averaged to calculate the CHAQ-DI total score which ranges from 0 (no or minimal physical dysfunction) to 3 (very severe physical dysfunction), higher score indicates more disability. Change from baseline at Weeks 2, 4, 8, 12 and 18 in DI total score is reported.

CHAQ: valid assessment of functional disability, discomfort in participants with rheumatic diseases. It comprises of three indices: Disability and Discomfort, and global assessment of arthritis (overall well-being). CHAQ-DI: as a measure of functional ability, consists of 30 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities-distributed, among a total of 30 items. Each question was rated on a 4-point scale of difficulty in performance ranges from 0 (no difficulty) to 3 (unable to do). To calculate overall score, participant must have a domain score in at least 6 of the 8 domains. Scores of 8 domains were averaged to calculate the CHAQ-DI total score which ranges from 0 (no or minimal physical dysfunction) to 3 (very severe physical dysfunction), higher score indicates more disability. Change from double-blind baseline at Weeks 20, 24, 28, 32, 36, and 40 in DI total score is reported.

CHAQ is a validated instrument and comprises of two indices, Disability and Discomfort, and global assessment of arthritis (overall well-being). Discomfort Index included: assessment of discomfort, the parent/legal guardian/participant were asked to provide a response to the question: How much pain do you think your child had because of his or her illness in the past week?, The parent/legal guardian/ participant rated the overall pain on a 0 to 10 VAS, where '0' indicates 'No Pain' and '10' indicates 'Very Severe Pain', higher scores indicates more severity.

CHAQ is a validated instrument and comprises of two indices, Disability and Discomfort, and global assessment of arthritis (overall well-being). Discomfort Index included: assessment of discomfort, the parent/legal guardian/participant were asked to provide a response to the question: How much pain do you think your child had because of his or her illness in the past week?, The parent/legal guardian/ participant rated the overall pain on a 0 to 10 VAS, where '0' indicates 'No Pain' and '10' indicates 'Very Severe Pain', higher scores indicates more severity.

Uveitis is the inflammation of the uvea. Participants were assessed for presence of uveitis (according to Standard Uveitis Nomenclature [SUN]). If Uveitis was present in participant at Baseline, it was considered as "active uveitis"; If Uveitis was not present in participant at Baseline, it was considered as "Inactive uveitis". As per SUN, Uveitis is defined as: anterior (in which anterior chamber is primary site of inflammation); intermediate (primary site of inflammation: vitreous); posterior (primary site of inflammation: retina or choroid). Percentage of participants with active uveitis (of any type) are reported.

Uveitis is the inflammation of the uvea. Participants were assessed for presence of uveitis (according to Standard Uveitis Nomenclature [SUN]). If Uveitis was present in participant at Baseline, it was considered as "active uveitis"; If Uveitis was not present in participant at Baseline, it was considered as "Inactive uveitis". As per SUN, Uveitis is defined as: anterior (in which anterior chamber is primary site of inflammation); intermediate (primary site of inflammation: vitreous); posterior (primary site of inflammation: retina or choroid). Percentage of participants with active uveitis (of any type) are reported.

Participants with enthesitis-related arthritis (ERA) undergo Tender entheseal assessment. Tender entheseal assessment: Entheses were assessed and coded as: 1= any tenderness, 0= no tenderness, NE= not evaluable. Total number of tender entheses: 66*(total number of tender entheses with counts > 0)/number of non-missing tender entheses. If > 33 tender entheseal counts were missing, total number of tender entheses was defined as missing.

Participants with ERA undergo Tender entheseal assessment. Tender entheseal assessment: Entheses were assessed and coded as: 1= any tenderness, 0= no tenderness, NE= not evaluable. Total number of tender entheses: 66*(total number of tender entheses with counts > 0)/number of non-missing tender entheses. If > 33 tender entheseal counts were missing, total number of tender entheses was defined as missing.

Participants with ERA undergo Modified Schober's Test. In the Modified Schober's Test, a mark was placed 5 cm below the midpoint of a line that joined the posterior superior iliac spines. Another mark was placed 10 cm above the first. The participant then bent maximally forward with the knees fully extended. The distance between the two marks was then re-measured. The full measurement between the two lines was recorded to the nearest tenth of a centimeter and is reported.

Participants with ERA undergo Modified Schober's Test. In the Modified Schober's Test, a mark was placed 5 cm below the midpoint of a line that joined the posterior superior iliac spines. Another mark was placed 10 cm above the first. The participant then bent maximally forward with the knees fully extended. The distance between the two marks was then re-measured. The full measurement between the two lines was recorded to the nearest tenth of a centimeter and is reported.

Participants with ERA undergo Overall Back Pain and Nocturnal Back Pain assessment. For Overall Back Pain, parent/legal guardian/participant were asked to provide a response to the question: What is the amount of back pain at any time that your child experienced in the past week? And For Nocturnal Back Pain: What is the amount of back pain at night that your child experienced in the past week?. Response to these questions was provided by parent/legal guardian/participant using a VAS of 0-10, where 0= No Pain and 10= Most Severe Pain, higher score indicated more severe pain.

Participants with ERA undergo Overall Back Pain and Nocturnal Back Pain assessment. For Overall Back Pain, parent/legal guardian/participant were asked to provide a response to the question: What is the amount of back pain at any time that your child experienced in the past week? And For Nocturnal Back Pain: What is the amount of back pain at night that your child experienced in the past week?. Response to these questions was provided by parent/legal guardian/participant using a VAS of 0-10, where 0= No Pain and 10= Most Severe Pain, higher score indicated more severe pain.

Percentage of body surface area affected by psoriasis was estimated using the palm method. One of the participant's palm to proximal interphalangeal (PIP) and thumb =\together represented 1% of total BSA. Regions of the body were assigned specific number of palms with percentage (Head and Neck = 10% [10 palms], Upper extremities = 20% [20 palms], Trunk [axillae and groin] = 30% [30 palms], Lower extremities [buttocks] = 40% [40 palms]). The number of palms of psoriatic skin in a body region was used to determine the extent (%) to which a body region was involved with psoriasis. The total BSA affected was the summation of individual regions affected.

Percentage of body surface area affected by psoriasis was estimated using the palm method. One of the participant's palm to PIP and thumb together represented 1% of total BSA. Regions of the body were assigned specific number of palms with percentage (Head and Neck = 10% [10 palms], Upper extremities = 20% [20 palms], Trunk [axillae and groin] = 30% [30 palms], Lower extremities [buttocks] = 40% [40 palms]). The number of palms of psoriatic skin in a body region was used to determine the extent (%) to which a body region was involved with psoriasis. The total BSA affected was the summation of individual regions affected.

The PGA of psoriasis was scored on a 6-point scale, reflecting a global consideration of the erythema, induration, and scaling across all psoriatic lesions. Average erythema, induration, and scaling were scored separately over the whole body according to a 5-point severity scale (0 [no symptom] to 5 [severe symptom]). The total score was calculated as average of the 3 severity scores and rounded to the nearest whole number score to determine the PGA score and ranged as 0= no symptom to 5=severe, higher score indicates more severity.

The PGA of psoriasis was scored on a 6-point scale, reflecting a global consideration of the erythema, induration, and scaling across all psoriatic lesions. Average erythema, induration, and scaling were scored separately over the whole body according to a 5-point severity scale (0 [no symptom] to 5 [severe symptom]). The total score was calculated as average of the 3 severity scores and rounded to the nearest whole number score to determine the PGA score and ranged as 0= no symptom to 5=severe, higher score indicates more severity.

Oral solution was given only to participants weighing <40 kg and to the participants who were unable to swallow tablets. Taste assessment was evaluated using a 5 categories questionnaire. Participants were asked to answer in one of the following categories to describe the taste of oral solution of tofacitinib: dislike very much, dislike a little, not sure, like a little and like very much. Number of participants within each category are reported.

Open-Label Phase: Number of Participants With Serious Infections, Cytopenia, Malignancies and Cardiovascular Diseases [ Time Frame: From the first dose of study drug up to Week 18 ]

Serious infection defined as any infection that requires hospitalization for treatment or requires parenteral antimicrobial therapy or meets other criteria that require it to be classified as a serious adverse event. Cytopenia was categorized as: lymphocyte counts: <500 lymphocytes/ millimeter^3 (mm), neutrophil counts <1000 neutrophils/mm^3, platelet counts <100,000 platelets/mm^3, any single hemoglobin value <8 grams/decilitre (g/dL) and any single hemoglobin value drops >=2 g/dL below baseline. Number of Participants With serious infections, cytopenia, malignancies and Cardiovascular Diseases are reported.

Double Blind Phase: Number of Participants With Serious Infections, Cytopenia, Malignancies and Cardiovascular Diseases [ Time Frame: From the first dose of study drug in double blind up to week 44 ]

Serious infection defined as any infection that requires hospitalization for treatment or requires parenteral antimicrobial therapy or meets other criteria that require it to be classified as a serious adverse event. Cytopenia was categorized as: lymphocyte counts <500 lymphocytes/mm^3, neutrophil counts <1000 neutrophils/mm^3, platelet counts <100000 platelets/mm^3, any single hemoglobin (hg) value <8 g/dL and any single hemoglobin value drops >=2 g/dL below baseline. Number of Participants With serious infections, cytopenia, malignancies and Cardiovascular Diseases are reported.

Tanner stage is a scale used to document the stage of development of puberty by assessing the secondary sexual characteristics: Pubic hair (both male and female), breast size (for females); and size of the genitalia (for males).were assessed in this study and with values in the scale ranging from: Stage 1: no hair, Stage 2: downy hair, Stage 3: Scant terminal hair, Stage 4: Terminal hair that fills the entire triangle overlying the pubic region and Stage 5: Terminal hair that extends beyond the inguinal crease onto the thigh. Tanner Stage for pubic hair at Day 1 was summarized and reported using number of participants in each stage.

Tanner stage is a scale used to document the stage of development of puberty by assessing the secondary sexual characteristics: Pubic hair (both male and female), breast size (for females); and size of the genitalia (for males) were assessed in this study and with values in the scale ranging from: Stage 1: no hair, Stage 2: downy hair, Stage 3: Scant terminal hair, Stage 4: Terminal hair that fills the entire triangle overlying the pubic region and Stage 5: Terminal hair that extends beyond the inguinal crease onto the thigh. Tanner Stage for pubic hair at Week 44 was summarized and reported using number of participants in each stage.

Tanner stage is a scale used to document the stage of development of puberty by assessing the secondary sexual characteristics: Pubic hair (both male and female), breast size (for females); and size of the genitalia (for males).were assessed in this study and with values in the scale ranging from: Stage 1: No glandular breast tissue palpable, Stage 2: Breast bud palpable under areola (1st pubertal sign in females), Stage 3: Breast tissue palpable outside areola; no areolar development, Stage 4: Areola elevated above contour of the breast, forming "double scoop" appearance, Stage 5: Areolar mound recedes back into single breast contour with areolar hyperpigmentation, papillae development and nipple protrusion. Tanner Stage for Breast at Day 1 was summarized and reported using number of participants in each stage.

Tanner stage is a scale used to document the stage of development of puberty by assessing the secondary sexual characteristics: Pubic hair (both male and female), breast size (for females); and size of the genitalia (for males).were assessed in this study and with values in the scale ranging from: Stage 1: No glandular breast tissue palpable, Stage 2: Breast bud palpable under areola (1st pubertal sign in females), Stage 3: Breast tissue palpable outside areola; no areolar development, Stage 4: Areola elevated above contour of the breast, forming "double scoop" appearance, Stage 5: Areolar mound recedes back into single breast contour with areolar hyperpigmentation, papillae development and nipple protrusion. Tanner Stage for Breast at Week 44 was summarized and reported using number of participants in each stage.

Open-Label Phase: Number of Participants With Tanner Staging Evaluation (Genitalia) [ Time Frame: Day 1 ]

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Layout table for eligibility information

Ages Eligible for Study:

2 Years to 17 Years (Child)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Male or female aged 2 to <18 years.

Must meet International League Against Rheumatism (ILAR) JIA diagnostic criteria for one of the following categories with active disease for at least 6 weeks:

Extended oligoarthritis;

Polyarthritis (RF+);

Polyarthritis (RF-);

Systemic JIA with active arthritis but without active systemic features in the prior 6 months and at the time of enrollment;

Psoriatic arthritis;

Enthesitis related arthritis. Subjects with polyarticular course JIA (ie, extended oligoarthritis, polyarthritis RF+, polyarthritis RF , systemic JIA with active arthritis but without active systemic features) must have a minimum of 5 active joints (an active joint is defined as a joint with swelling or, in the absence of swelling, limited range of motion accompanied by either pain on motion or tenderness) at screening and baseline to be eligible for study entry.

Subjects with psoriatic or enthesitis related arthritis must have a minimum of 3 active joints (an active joint is defined as a joint with swelling or, in the absence of swelling, limited range of motion accompanied by either pain on motion or tenderness) at screening and baseline to be eligible for study entry.

Treatment with stable doses of a Non Steroidal Anti inflammatory Drug (NSAID) and/or a stable dose of an oral glucocorticoid, and/or a stable dose of methotrexate is permitted.

For subjects receiving an oral glucocorticoid: Glucocorticoids may be administered at a maximum dose of 0.2 mg of prednisone equivalent per kilogram per day or 10 mg per day for ≥ 2 weeks before baseline, whichever is lower.

For subjects receiving methotrexate (MTX) treatment: MTX may be administered either orally or parenterally at doses not to exceed 25 mg/wk or 20 mg/m2/week (whichever is lower); participants must have taken MTX for 3 months and be at a stable dose for at least 6 weeks before baseline. Subjects taking MTX must be taking folic acid or folinic acid in accordance with local standards.

For subjects with psoriatic arthritis, the following topical treatments for psoriasis are allowed: non medicated emollients for use over the whole body; topical steroids including hydrocortisone and hydrocortisone acetate ≤1% for the palms, soles, face, and intertriginous areas only; tar, salicylic acid preparations, and shampoos free of corticosteroids are permitted only for the scalp

Inadequate response or intolerance to at least one Disease Modifying Anti Rheumatic Drug (DMARD), which may include MTX or biologic agents; in the case of ERA and psoriatic arthritis, inadequate response to Non Steroidal Anti Inflammatory Drugs (NSAIDs).

No evidence or history of untreated or inadequately treated active or latent tuberculosis (TB) infection as evidenced by the following:

A negative QuantiFERON ®TB Gold In Tube test performed within the 3 months prior to screening. A negative purified protein derivative (PPD) test can be substituted for the QuantiFERON® TB Gold In Tube test only if the central laboratory is unable to perform the test or cannot determine the results to be positive or negative and the Pfizer medical monitor is informed and agrees on a case by case basis.

Chest radiograph without changes suggestive of active tuberculosis (TB) infection within 3 months prior to screening is recommended and should be performed according to local standards of care or country-specific guidelines.

No history of either untreated or inadequately treated latent or active TB infection.

If a subject has previously received an adequate course of therapy for either latent (9 months of isoniazid in a locale where rates of primary multi drug resistant TB infection are <5% or an acceptable alternative regimen) or active (acceptable multi drug regimen) TB infection, neither a PPD test nor a QuantiFERON-Gold®TM test need be obtained. A chest radiograph should be obtained if not done within the 3 months prior to screening. To be considered eligible for the study, the chest radiograph must be negative for active tuberculosis infection.

A subject who is currently being treated for latent TB infection can only be enrolled with confirmation of current incidence rates of multi-drug resistant TB infection, documentation of an adequate treatment regimen, and prior approval of the Sponsor.

Fertile males and females who are, in the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) must be willing and able to use a highly effective method of contraception as outlined in this protocol during the study and for at least 28 days after the last dose of study medication.

6 Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

7. Evidence of a personally signed and dated Informed Consent document and Assent document (as appropriate) indicating that the subject and a legally acceptable representative/parent(s)/legal guardian has been informed of all pertinent aspects of the study.

Exclusion Criteria

Subjects with any of the following characteristics/conditions will not be included in the study:

Previous JIA treatment with tofacitinib.

Systemic JIA (sJIA) with active systemic features (including subjects with characteristic sJIA fever and rash or serositis within 6 months of enrollment).

Persistent oligoarthritis.

Undifferentiated JIA.

Infections:

Chronic infections;

Any infection requiring hospitalization, parenteral antimicrobial therapy or judged to be opportunistic by the investigator within the 6 months prior to the first dose of study drug;

Any treated infections within 2 weeks of Baseline visit;

A subject know to be infected with Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C;

History of infected joint prosthesis with prosthesis still in situ.

History of recurrent (more than one episode) herpes zoster or disseminated (at least one episode) herpes zoster, or disseminated (at least one episode) herpes simplex.

History of any other rheumatologic disease, other than Sjogren's syndrome..

History or current symptoms suggestive of lymphoproliferative disorders (eg, Epstein Barr Virus [EBV] related lymphoproliferative disorder, lymphoma, leukemia, or signs and symptoms of current lymphatic disease).

Vaccinated or exposed to a live or attenuated vaccine within the 6 weeks prior to the first dose of study drug, or is expected to be vaccinated or to have household exposure to these vaccines during treatment or during the 6 weeks following discontinuation of study drug.

Subjects without documented evidence of having received at least one dose of the varicella vaccine in countries where the vaccine is approved and standard of care or those who do not have evidence of prior exposure to varicella zoster virus (VZV) based on serological testing (ie, VZV IgG Ab).

Current malignancy or history of any malignancy with the exception of adequate treated or excised basal cell or squamous cell or cervical cancer in situ.

Subjects who have previously failed more than 3 biologic therapies (with different mechanisms of action) for JIA.

Subjects with a first degree relative with a hereditary immunodeficiency; IgA deficiency not exclusionary.

Recent (within 28 days prior to first dose of study drug) significant trauma or major surgery.

Subjects receiving potent and moderate CYP3A4 inhibitors or inducers.

Prior treatment with non B cell specific lymphocyte depleting agents/therapies (eg, almetuzumab [CAMPATH], alkylating agents [eg, cyclophosphamide or chlorambucil], total lymphoid irradiation, etc.). Subjects who have received rituximab or other selective B lymphocyte depleting agents (including experimental agents) are eligible if they have not received such therapy for at least 1 year prior to study baseline and have normal CD 19/20+ counts by FACS analysis.

Use of prohibited prescription or non prescription drugs and dietary supplements listed in Appendix 1 and Appendix 4 within the specified time frame prior to the first dose of study medication.

Herbal supplements must be discontinued at least 28 days prior to the first dose of study medication.

Use of certain biologic and non biologic DMARDs are disallowed at any time during this study (Appendix 1).

For subjects with PsA, oral and topical medications and alternative treatments that could affect psoriasis are prohibited (see Inclusion Criterion 2 for exceptions). This includes topical corticosteroids, tars, keratolytics, anthralin, vitamin D analogs, and retinoids which must be discontinued at least 2 weeks prior to first dose of study drug. Also prohibited is ultraviolet B (UVB) (narrowband or broadband) phototherapy that must be discontinued at least 2 weeks prior to first dose of study drug. Psoralens + ultraviolet A (UVA) phototherapy (PUVA) must be discontinued at least 4 weeks prior to first dose of study drug.

Subjects who are children of or related to investigational site staff members, site staff members otherwise supervised by the investigator, or Pfizer employees directly involved in the conduct of the study.

Participation in other studies involving investigational drug(s) within 4 weeks or 5 half lives (whichever is longer) prior to study entry and/or during study participation. Exposure to investigational biologics should be discussed with the Sponsor.

Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.